2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and a process for the preparation thereof

ABSTRACT

The present invention relates to the compound of formulae ##STR1## and to a process for the manufacture of compounds of the general formula ##STR2## which are ligands for the metabotropic glutamate receptors of group II, wherein 
     T is tritium; 
     R 1  is hydroxy, lower alkoxy, lower alkenyloxy, benzyloxy, hydrogen, deuterium or tritium; 
     R 11  is hydrogen, deuterium or tritium, hydroxy or amino, and 
     R 2  is hydrogen or tritium, or 
     R 1  and R 2  form a bond.

FIELD OF THE INVENTION

The present invention relates to ligands for the metabotropic glutamatereceptors of Group II and methods for making the ligands.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor. L-glutamic acid, the most commonlyoccurring neurotransmitter in the CNS, plays a critical role in a largenumber of physiological processes. The glutamate-dependent stimulusreceptors are divided into two main groups. The first main group formsligand-controlled ion channels. The metabotropic glutamate receptors(mGluR) belong to the second main group and, furthermore, belong to thefamily of G-protein-coupled receptors.

At present, eight different members of these mGluRs are known and ofthese some even have sub-types. On the basis of structural parameters,the different second messenger signaling pathways and the differentaffinities to low-molecular weight chemical compounds, these eightreceptors can be sub-divided into three sub-groups: mGlu1 and mGlu5belong to group I, mGlu2 and mGlu3 belong to group II and mGlu4, mGlu6,mGlu7 and mGlu8 belong to group III.

Generally, these receptors function to modulate the presynaptic releaseof glutamate, and the postsynaptic sensitivity of the neuronal cell toglutamate excitation. The metabotropic glutamate receptors are usefultargets for the treatment of acute and chronic neurological conditionsand psychiatric disorders.

Ligands for the metabotropic glutamate receptors are described, forexample, in EP 774 455. Compounds described therein are useful asmodulators of metabotropic glutamate receptor function. These compoundsdiffer from compounds of the present formula I by one or twosubstitutions on the ring molecule. The syntheses described forgenerically encompassed compounds are very uncertain and vague, and theylead to mixtures of diastereomers and/or enantiomers which would have tobe separated into dean isomers by tedious and time-consuming procedures.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of acompound of formula ##STR3## wherein R¹ is hydroxy, lower alkoxy, loweralkenyloxy, benzyloxy, hydrogen, deuterium or tritium,

R¹¹ is hydrogen, deuterium, tritium, hydroxy or amino, and

R² is hydrogen or tritium, or

R¹ and R² form a bond,

which process comprises:

a) reacting a compound of formula ##STR4## with a reducing agent, toobtain a compound of formula VII and a compound of formula X ##STR5##wherein R'" and R" are each independently selected from benzyl or loweralkyl, and then, starting with either or both the compounds of formulaVII and X,

b) reacting with a reducing agent to reduce the azide group, and

c) hydrolyzing the ester groups,

to obtain a compound of formula I.

The process of producing a compound of formula I according to thepresent invention can also include, after step a):

d) reacting either or both the compound of formula VII or X withtrifluoromethane sulfonic acid anhydride to obtain a resultant, and then

e) reacting the resultant of step d) in a base to obtain a compound offormula XXVI ##STR6## and f) treating with a gas selected from the groupconsisting of hydrogen and tritium gas and a mixtures thereof.

The process of producing a compound of formula I according to thepresent invention can alternatively include, after step a):

g) reacting either or both the compound of formula VII or X withtrifluoromethane sulfonic acid anhydride to obtain a resultant, and then

h) reacting the resultant of step g) with a reagent having an azidegroup in a polar, aprotic solvent, to obtain a compound of formulaXXVIII ##STR7##

The process of producing a compound of formula I according to thepresent invention can alternatively include, after step a):

i) alkylating, alkenylating or benzylating either or both the compoundof formula VII or X.

The present invention also provides compounds of formulae ##STR8## inwhich R" and R'" are each independently selected from benzyl or loweralkyl and wherein compounds of formula VII and intermediates for thepreparation of formula I compounds.

The present invention further provides a method of controlling orpreventing neurological diseases or psychiatric disorders comprisingadministering to a patient in need of treatment an effective amount ofthe compound of formula I-A. An effective dose is, for example, fromabout 1 mg to about 1000 mg per day for an average patient weighing 70kg.

DETAILED DESCRIPTION OF THE INVENTION

The Present invention is directed to compounds of formulae ##STR9## andto a process for the manufacture of compounds of the general formula##STR10## wherein T is tritium;

R¹ is hydroxy, lower alkoxy, lower alkenyloxy, benzyloxy, hydrogen,deuterium or tritium;

R¹¹ is hydrogen, deuterium or optionally tritium, hydroxy or amino and

R² is hydrogen or optionally tritium or

R¹ and R² form a bond.

Compounds of general formula I are ligands for the metabotropicglutamate receptors of group II.

It has now surprisingly been found that compounds of the general formulaI can be prepared in high yield and in high diastereoisomeric andenantiomeric purity in a new synthetic way.

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term "lower alkyl" denotes a straight- orbranched-chain alkyl group containing from 1-6 carbon atoms, forexample, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl,pentyl or hexyl.

Also, the term "lower alkenyl" denotes the same kind of straight- orbranched-chain moiety as described with "lower alkyl", but containingmultiple bond(s).

The term "leaving group" means, for example, an iodide-, bromide-,chloride-, methanesulfonate-, tolylsulfonate- ortrifluoromethanesulfonate-group.

The term "halogen" denotes chlorine, iodine, fluorine or bromine.

The present invention also provides compounds of formulae ##STR11## inwhich R" and R'" are independently from each other benzyl or loweralkyl, wherein compounds of formula VII are used as intermediates forthe process for preparation of compounds of formulae I-A and I.

In accordance with the present invention, compounds of formula I-A areused for the control or prevention of acute and chronic neurologicalconditions and psychiatric disorders. In accordance with the presentinvention, compounds of formulae I-B and I-C can be used as radioligands in a binding assay in order to screen chemical libraries toidentify further structures of potential interest.

In accordance with the present invention, the process comprises

A) reducing the carbonyl group of a compound of formula ##STR12## to ahydroxy group of a compound of formula VII and formula X ##STR13##wherein R'" and R" are independently from each other benzyl or loweralkyl, and, if desired,

B) i) replacing the hydroxy group of a compound of formula VII or X witha leaving group, and

ii) eliminating the leaving group to obtain a compound of formula XXVI,or

iii) substituting said leaving group with azide to obtain a compound offormula XXVIII, ##STR14## and if desired, C) alkylating, alkenylating orbenzylating a compound of formula VII or X and

D) reducing the azide group(s) into (an) amino group(s), for example,reducing the azide group of formula XXVI to obtain a compound of formulaXXVII, or reducing the azide groups of formula XXVIII to obtain acompound of formula XXIX, ##STR15## and E) hydrolyzing the ester groups,for example, hydrolyzing the ester groups of the compound of formulaXXVII or XXIX to a compound of formula I-10 or to a compound of formulaI-12, respectively ##STR16## and F) where a compound having ring with adouble bond results, for example, a compound of formula XXVI or I-10,hydrogenating the double bond with hydrogen, tritium or hydrogen andtritium gas.

Enantiomeric selectivity is achieved, for example, in step b)iii), inwhich a compound of formula XXVIII results.

In the following schemes 1-5 are described the processes for preparationof the starting compound of formula VII to compounds of formulae I-A,I-B, and I-C and processes for preparation of compounds of formula I.##STR17## wherein Bn is benzyl.

According to scheme 1, compounds of general formula VII can be preparedfrom compounds of general formula ##STR18## by reacting with an azide,preferably sodium azide in a polar, aprotic solvent, like for exampledimethylformamide (DMF), at temperatures of around 100° C. or in aqueoussolutions of water-miscible solvents, like for example acetone ortetrahydrofuran, at temperatures around 50° C. and then hydrolyzing theformed sulfate half ester with an acid, preferably sulfuric acid.

An example for this kind of transformation can be found in J. Am. Chem.Soc. 1988, 110 (22), 7538.

Compounds of general formula VI can be prepared by reacting compounds ofgeneral formula V ##STR19## with thionyl chloride in an aprotic solventto yield a cyclic sulfite. If desired, the reaction can be carried outin the presence of a base. Then the cyclic sulfite is oxidized to thecyclic sulfate. Suitable solvents for the formation of the sulfite are,for example, chlorinated solvents such as dichloromethane, chloroform,carbon tetrachloride or dichloroethane. Suitable bases can be selectedfrom amines, for example, but not limited to, triethylamine ordiisopropylethylamine. A preferred oxidant is, for examplesodium-periodate in the presence of catalytic amounts of a rutheniumsalt, such as ruthenium trichloride. The oxidation is preferably carriedout in a solvent mixture consisting of carbon tetrachloride,acetonitrile and water in a ratio of from about 1:1:1 to about 2:2:3.

A procedure for the preparation of cyclic sulfates can be found in U.S.Pat. No. 5,321,143.

Compounds of general formula V can be prepared by performing anasymmetric cishydroxylation (Sharpless AD) reaction on compounds ofgeneral formula ##STR20## This reaction allows for the selectivepreparation of one desired isomer of compounds of general formula V outof four possible isomers (two diastereoisomeric pairs of enantiomers).Examples for the use of the asymmetric cis-hydroxylation reaction can befound in for example J. Org. Chem. 1996, 61(8), 2582-2583 andTetrahedron:Asymmetry 1993, 4(1), 133-141.

Compounds of general formula IV can be prepared from compounds ofgeneral formula ##STR21## by a transition metal catalyzed carbonmonoxide insertion in the presence of the alcohol

    R'"--OH.

wherein R'" is benzyl or lower alkyl,

The reaction can be carried out in R'"--OH as the solvent or aproticsolvents such as, for example tetrahydrofuran or DMF with stochiometricamounts (one to two equivalents) of R'"--OH present. The transitionmetal preferred is palladium in the form of its salt, like for examplepalladium(II)-acetat or palladium(0)-compounds, an example of which istetrakis(triphenylphosphine)palladium. Examples for such kind ofCO-insertions can be found in J. Org. Chem. 1992, 57, 5979.

Compounds of general formula III can be prepared by methods known in theart by reacting a carbonyl compound of general formula ##STR22## with abase in the presence of N-phenianesulfonimide) ortrifluoromethanesulfonic acid anhydride. The base can be selected fromsterically hindered amines, for example 2,6-di-tert.-butyl pyridine orfrom amides, such as lithium diisopropyl amide. The reaction can becarried out at temperatures between -78° and +20° C. In the case ofamine bases, the solvent can be selected from the class of chlorinatedsolvents, such as, for example, dichloromethane, chloroform or1,2-dichloroethane. In the case of the amide bases, the solvent can beselected from the class of ethers, for example diethyl ether ortetrahydrofuran.

A general method for the preparation of vinyl-trifluoromethanesulfonatescan be found in J. Org. Chem. 1992,57, 5979.

According to the present invention, compounds of general formula I inwhich R² is hydrogen and R¹ and R¹¹ have the meaning as described above,can be prepared by reducing the azide group of an azide-containingstarting compound to an amino group. For example, the azide group ofcompounds of general formula VII can be reduced to the amino group toobtain compounds of general formula VIII. Ester groups are hydrolyzed tothe carboxylic acids. For example, the compounds of general formula VIIIcan be hydrolyzed to the carboxylic acids as compound I-A. It is alsopossible to cleave the esters to obtain the carboxylic acids prior toreducing the azide group. For example, compounds of formula VII-I can becleaved to obtain compounds of general formula XI (cf scheme 2), andsubsequently reduce the azide group to the amino group.

A practical method for the reduction of azides to amines is for examplethe catalytic hydrogenation in the presence of a transition metalcatalyst, like for example nickel, platinum or palladium (see forexample Org. Syntheses, Coll. Vol. V, 1973, 586). Another suitablemethod is the Staudinger-type reduction of azides using phosphines, likefor example triphenyl phosphine in aqueous solutions of an ether, likefor example tetrahydrofuran, as described in J. Chem. Soc. Chem. Comm.1986, 409. Still another method for the reduction of azides to amines isthe treatment with metal hydrides, like for example lithiumaminoborohydride, as shown in: ACS Symp. Ser. 1996, 641 (Reductions inOrganic Synthesis), 153-166), or sodium borohydride in the presence of atransition metal salt, like for example nickel(II)chloride hexahydrate,as shown in Chem. Ind. (London) 1987, 764.

The cleavage, i.e., hydrolysis, of the ester groups in accordance withthe present invention can be achieved by using methods known to thoseskilled in the art, for example, by treatment of the starting ester withaqueous acid or base at ambient or elevated temperatures, or by thecleavage of esters sensitive to catalytic hydrogenation (for example,benzyl esters and the like) using hydrogen in the presence of atransition metal catalyst like for example nickel, platinum orpalladium. ##STR23## wherein D is deuterium and T is tritium.

According to scheme 2 compounds of general formula I can also beprepared by reducing a compound of the following general formula,wherein moieties R, R', R" and R'" are as shown in scheme 2, as incompounds of formula IX-1, XVI and XIII such that R" and R'" are eachindependently selected from benzyl or lower alkyl and R and R' are bothN, or R is H and R' is an acyl group, ##STR24## with a reducing agent,for example with sodium-borohydride, lithium- borohydride,sodium-borodeuteride, lithium-borodeuteride, sodium-borotritiide andlithium-trimethoxyborotritiide in the presence or absence of ceriumtrichloride. The reaction is carried out in solvent mixtures of a proticsolvent, for example an alcohol, such as methanol or ethanol, and anether, such as diethylether or tetrahydrofuran, at temperatures between-78° and +30° C. Although not shown within scheme 2, a compound offormula IX (such as formula IX-1), can be reduced to obtain a compoundof formula VII and a compound of formula X (such as formula X-1 asshown). Variation of the conditions of the reduction reaction such assolvent composition, the temperature, the reducing agent used, thepresence or absence of cerium trichloride, as well as the transformationof the azide into an N-acylamino group by a reaction prior to reductionof the ketone, like for example the shown reaction of IX to XVI bytreatment with thioacetic acid as described in J. Org. Chem. 1988, 53,1581, allows one skilled in the art to obtain the desireddiastereoisomer of compounds of general formula I, in which R¹represents hydroxy, R¹¹ represents hydrogen, deuterium or tritium and R²represents hydrogen.

A comprehensive overview for the use of reducing agents can be found inLarock, Comprehensive Organic Transformations, Verlag Chemie 1989, 527.

Compounds of general formula IX can be prepared by oxidizing a compoundof general formula VII. The reaction is carried out in a chlorinatedsolvent, for example in dichloromethane, chloroform or dichloroethane.Suitable oxidizing agents are, for example derivatives of chromic acid,such as PDC or PCC, or hypervalent iodine-compounds, such as IBX or theDess-Martin-reagent. The reaction is preferably carried out attemperatures between -20° and +30° C. under an inert atmosphere.

A comprehensive overview for oxidations using the reagents describedabove can be found in R. C. Larock, Comprehensive OrganicTransformations, Verlag Chemie 1989, 604. ##STR25##

According to scheme 3 the O-alkylated compounds of general formula I,wherein R³ is lower alkyl (I-7 and I-8), lower alkenyl (I-9) or benzyl(I-10) can be prepared from compounds of the general formulae XXIII(XXIII-1 with R³ ═CH₃ ; XXIII-2 with R³ ═allyl; and XXIII-3 with R³═benzyl;)and XXIV (XXIV-1 with R³ ═CH₃ ; XXIV-2 with R³ ═allyl; andXXIV-3 with R³ ═benzyl;)by the methods described above for thepreparation of compound I-A.

Compounds of general formula XXIII in which R³ represents lower alkyl,lower alkenyl or benzyl can be prepared by reacting a compound ofgeneral formula VII-1 with a trichloroacetimidate of general formula##STR26## in which R³ represents lower alkyl, lower alkenyl or benzyl inan aprotic solvent in the presence of an acid. In this manner a compoundof formula VII can be alkylated, alkenylated or benzylated.

The acid, which is preferably used in catalytic amounts, can be aBronsted-acid such as trifluoromethane sulfonic acid or trifluoroaceticacid or a Lewis-acid such as trimethylsilyl-trifluoromethane sulfonateor borontrifluoride-etherate. Suitable solvents are preferably aproticsolvents like ethers, such as diethylether or tetrahydrofuran,chlorinated solvents, such as for example dichloromethane, chloroform ordichloroethane, or mixtures of chlorinated solvents and hydrocarbons,such as hexane or cyclohexane. The reaction can be carried out attemperatures between -50° and +40° C. under an inert atmosphere.

Another way to prepare the compounds of general formula I in which R¹represents lower alkyl, lower alkenyl or benzyl is the treatment ofcompounds of general formula VII with a trifluoromethanesulfonate ofgeneral formula ##STR27## in which R³ has the meaning as describedabove, in a suitable solvent and in the presence of a base. This isanother way in which a compound of formula VII can be alkylated,alkenylated or benzylated.

The base can be selected from the group of sterically hindered amineslike, for example, but not limited to, 2,6-di-tert.-butyl-pyridine. Thereaction is preferably carried out in aprotic solvents, for exampleethers, such as diethylether or tetrahydrofuran, chlorinated solvents,for example dichloromethane, chloroform or dichloroethane or mixtures ofchlorinated solvents or hydrocarbons, for example hexane or cyclohexane.The reaction is preferably carried out at temperatures between -50° and+50° C. under an inert atmosphere.

Still another way to alkylate, alkenylate or benzylate a compound offormula VII and thus prepare compounds of general formula XXIII in whichR³ represents lower alkyl, lower alkenyl or benzyl, is the treatment ofcompounds of general formula VII with electrophilic agents of generalformula

    R.sup.3 --X

in which R³ has the meaning as described above and X represents aleaving group, for example iodide, bromide, methanesulfonate andtolylsulfonate, in a suitable solvent in the presence of a base. Thereaction is preferably carried out in polar, aprotic solvents, forexample chlorinated solvents such as dichloromethane, chloroform ordichloroethane, or amides, for example, dimethylformamide andN-methyl-pyrrolidinone. The base can be selected from the group ofsterically hindered amines, for example, but not limited to,2,6-di-tert.-butyl-pyridine or from the hydride-type such as, forexample, sodium hydride or potassium hydride. Other possible bases canbe selected from the group of amides, such as for example, sodiumhexamethyl disilazide or lithium diisopropylamide. The reaction ispreferably carried out at temperatures between -50° and +50° C. under aninert atmosphere. ##STR28##

According to scheme 4 compounds of general formula I, in which R¹represents hydrogen and R¹¹ and R² represent tritium can be prepared bytreating a compound of general formula ##STR29## with a mixture ofhydrogen and tritiunrence of a transition metal. If desired, the estergroups may be transformed to the carboxylates prior to the concomitantreduction of the azide group.

Compounds of general structure ##STR30## can be prepared by reducing theazide group in compounds of general formula XXVI using the reagents andconditions as described above, preferably with trimethylphosphine as thereducing agent. The reduction is preferably carried out under theconditions as described above for the use of triphenylphosphine. Thenthe ester groups can be transformed into carboxylic acids by the methodsas described above. Again, if desired, the ester groups may betransformed to the carboxylates prior to the reduction of the azidegroup.

Compounds of general formula XXVII can be prepared by eliminating theanion of trifluoromethane sulfonic acid from a compound of generalformula ##STR31## in the presence of a base.

The reaction can be carried out in aprotic solvents, for example ethers,such as diethyl ether or tetrahydrofuran at temperatures between 20° and35° C. (diethylether), respectively 20° and 50° C. (tetrahydrofuran).The base may be selected from the amine bases, like for example DBU andthe like.

Compounds of general formula XXV may be prepared by converting compoundsof general formula VII into their trifluoromethanesulfonyl esters.Formula VII can be reacted with trifluoromethane sulfonic acidanhydridesuch that the hydroxy group is transformed into a leavinggroup, as in the case of formula XXV, trifluoro-methyl sulfonic estergroup. The reaction is a standard reaction in organic chemistry and canbe carried out as described in Larock, Comprehensive OrganicTransformations, Verlag Chemie 1989, 360. ##STR32##

According to scheme 5 compounds of general formula I, in which R¹ and R²represent hydrogen and R¹¹ represents amino can be prepared fromcompounds of general formula ##STR33## by reduction of the azide groupsusing the reagents and conditions as described above. Then the estergroups can be transformed into carboxylic acids by the methods asdescribed above. If desired, the ester groups may be transformed to thecarboxylates prior to the reduction of the azide groups.

Compounds of general formula XXVIII can be prepared by substituting thetrifluoromethyl sulfonyl group in compounds of general formula ##STR34##with an azide-containing reagent, preferably sodium azide, in a polar,aprotic solvent like for example DMF at temperatures of around 60° to100° C.

Compounds of formula I-A may be used in the control or prevention ofacute and chronic neurological conditions and psychiatric disorders. In"Mol. Pharmacology, Vol.53, 228-233, (1998)" it is described the invitro binding of a selective group II metabotropic glutamate receptorradioligand, [3H]LY354740 in rat brain. The inhibition by LY354740 wasantagonised with the group II selective competitive antagonist of thecompound of formula I-A (pKB=6.0; Ki mGluR2=0.052 μM; Ki mGluR3=0.089μM).

The compounds of formula I and their salts, as herein described, can beincorporated into standard pharmaceutical dosage forms, for example, fororal or parenteral application with the usual pharmaceutical adjuvantmaterials, for example, organic or inorganic inert carrier materials,such as, water, gelatin, lactose, starch, magnesium stearate, talc,vegetable oils, gums, polyalkylene-glycols and the like. Thepharmaceutical preparations can be employed in a solid form, forexample, as tablets, suppositories, capsules, or in liquid form, forexample, as solutions, suspensions or emulsions. Pharmaceutical adjuvantmaterial can be added and include preservatives, stabilizers, wetting oremulsifying agents, salts to change the osmotic pressure or to act asbuffers. The pharmaceutical preparations can also contain othertherapeutically active substances.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In the case of oraladministration the dosage lies in the range of about from 1 mg per daydosage to about 1000 mg per day of a compound of general formula I for apatient weighing about 70 kg, although the upper limit can also beexceeded when this is shown to be indicated. In particular, the compoundof formula I-A can be used to control or prevent acute or chronicneurological conditions or psychiatric disorders by administering to apatient in need of treatment an amount of from about 1 mg to about 1000mg per day of the compound of formula I-A.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE 1(1RS,5SR,6RS)-2-Trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-carboxylicacid ethyl ester (III)

To a solution of diisopropylamine (11.94 mL, 84.6 mmol) in THF (77 mL)was added dropwise n-BuLi (47.6 mL, 76.1 mmol, 1.6 M solution in hexane)at 0° C. and stirred for 10 min at 0° C. After cooling to -78° C. asolution of (1S,5R,6S)-2-oxo-bicyclo[3.1.0]hexane-6-carboxylic acidethyl ester (II) (11.86 g, 70.5 mmol) in THF (39 mL) was added dropwisewithin 25 min. Stirring was continued at -78° C. for 1 h, whereupon asolution of N-phenyl-bis(trifluoromethylsulfonyl)imine (27.7 g, 77.5mmol) in THF (83 mL) was added and then stirred for 90 min at 23° C.Aqueous workup with ether, sat. NaHCO₃ -sol., brine, drying over Na₂SO₄, removal of the solvent under vacuum left an orange-brown oil, whichwas purified by silica gel column chromatography with hexane/ethylacetate 9:1 to give(1RS,5SR,6RS)-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-carboxylicacid ethyl ester (III) (18.47 g, 87%) as a slightly brown oil. ¹ H-NMR(250 MHz, CDCl₃) □1.27 (3H, t, J=7.1 Hz), 1.46 (1H, m), 2.28 (1H, m),2.55 (2H, m),2.79 (1H, m), 4.15 (2H, q, J=7.1 Hz), 5.4 (1H, m); MS[EI]300 (M⁺).

EXAMPLE 2 (1RS,5SR,6RS)-Bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (IV)

A solution of(1RS,5SR,6RS)-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-carboxylicacid ethyl ester (III) (14.48 g, 48.2 mmol), Pd(OAc)₂ (326 mg, 1.45mmol), PPh₃ (760 mg, 2.9 mmol), benzyl alcohol (10.0 mL, 96.5 mmol) andEt₃ N (13.5 mL, 96.5 mmol) in DMF (195 mL) was purged with CO for 10 minand then stirred for 5 h at 23° C. under a balloon with CO. Aqueousworkup with ether, 1 N HCl-sol., sat. NaHCO₃ -sol. and brine wasfollowed by drying over MgSO₄. Removal of the solvent under vacuum lefta dark brown oil, which was purified by silica gel column chromatographywith hexane/ethyl acetate 9:1 to yield(1RS,5SR,6RS)-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid 2-benzylester 6-ethyl ester (IV) (10.36 g, 75%) as a yellow oil. ¹ H-NMR (250MHz, CDCl₃) □1.13 (1H, m), 1.26 (3H, t, J=7.1 Hz), 2.25 (1H, m), 2.64(1H, m), 2.79-2.91 (2H, m), 4.10 (2H, q, J=7.1 Hz), 5.18 (1H, d, J=12Hz), 5.24 (1H, d,J=12 Hz), 6.58 (1H, bs), 7.30-7.40 (5H, m); MS[EI]286(M⁺).

EXAMPLE 3(1S,2S,3R,6S)-2,3-Dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (V)

A solution of (1RS,5SR,6RS)-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (IV) (11.69 g, 40.4 mmol), K₂ [OsO₂(OH)₄ ](99 mg, 0.27 mmol), (DHQD)₂ PHAL (1.05 g, 1.35 mmol), K₃ Fe(CN)₆(26.6 g, 80.8 mmol), K₂ CO₃ (11.2 g, 80.8 mmol) and MeSO₂ NH₂ (11.53 g,121.2 mmol) in tert.-butanol (140 mL) and H₂ O (140 mL) was stirredvigorously at 4° C. for 24 h. After addition of Na₂ SO₃ (40.4 g) andstirring for 30 min at 23° C. the mixture was diluted with water (300mL) and extracted with ethyl acetate (3×300 mL). The combined organiclayers were washed with 2 N NaOH-sol. (200 mL) and brine (200 mL)followed by drying over Na₂ SO₄. Removal of the solvent under vacuumleft a dark brown solid (13.51 g), which was subjected to silica gelcolumn chromatography with hexane/ethyl acetate 2:1->3:2->1:1 to yieldthe residual starting material as a yellow oil (3.58 g, 31%, 65% ee),the undesired diastereomeric diol as a yellow oil (1.30 g. 10%) and thecrystalline diol (1S,2S,3R,6S)-2,3-dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (5.91g, 45.7%, 63% ee) as a pale yellow solid. The latter material was twicerecrystallized from ethyl acetate/ether/hexane to give enantiopure(1S,2S,3R,6S)-2,3-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (V) (3.36 g, 26%, >99% ee) as whiteneedles. ¹ H-NMR (250 MHz, CDCl₃) □1.24 (3H, t, J=7.1 Hz), 1.80-1.92(2H, m), 1.99 (1H, m), 2.08 (1H, dd, J=6.9,2.9 Hz), 2.30-2.38 (2H, m),3.82 (1H, s), 4.10 (2H, q, J=7.1 Hz), 5.20 (1H, d, J=12.3 Hz), 5.34 (1H,d, J=12.3 Hz), 7.36 (5H, bs); MS[ISP]321 (M+H⁺); mp 112-114° C. □_(D) ²⁰-73.35°(c=1.17, CHCl₃).

EXAMPLE 4 (1S,1aS,1bS,4aR,5aR)-3,3-Dioxo-tetrahydro-2,4-dioxa-6-thia-cylopropa[a]pentalene-1,1b-dicarboxylicacid 1b-benzul ester 1-ethyl ester (VI)

To a solution of(1S,2S,3R,6S)-2,3-dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (V) (2.66 g, 8.32 mmol) in CH₂ Cl₂ (14 mL)at 0° C. was added SOCl₂ (1.21 mL, 16.64 mmol) and stirring wascontinued at 40° C., until tlc indicated complete conversion to thecyclic sulfite. The solvent and excess SOCl₂ were removed under vacuum,the residual oil was dissolved in CC1₄ (8.3 mL), CH₃ CN (8.3 mL) and H₂O (12.5 mL) and cooled to 0° C. NaIO₄ (2.67 g, 12.5 mmol) and RuCl₃hydrate (33 mg) were added and the mixture was stirred at 23° C. for 30min. Aqueous workup with ether, water and brine was followed stirring ofthe organic phase with MgSO₄ and a spatula tip of activated carbon.After filtration throught celite the solvent was removed under vacuum toyield a pale the crude cyclic sulfate as a brown oil (3.31 g). Ananalytical sample was obtained by silica gel column chromatography withhexane/ethyl acetate 2:1 to yield(1S,1aS,1bS,4aR,5aR)-3,3-dioxo-tetrahydro-2,4-dioxa-6-thiacyclopropa[a]pentalene-1,1b-dicarboxylicacid 1b-benzyl ester 1-ethyl ester (VI) (98%). ¹ H-NMR (250 MHz, CDCl₃)□1.25 (3H, t,J=7.2 Hz), 1.67 (1H, t, J=3.5 Hz), 2.28 (1H, m), 2.52-2.62(3H, m), 4.11 (2H, m), 5.32 (2H, s), 7.38 (5H, s); MS[ISP]400 (M+NH₄ ⁺);□_(D) ² 36.08°(c=1.13, CHCl₃).

EXAMPLE 5 (1S,2R,3R,5R,6S)-2-Azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1)

The crude cyclic sulfate VI was dissolved in acetone (45 mL) and H₂ O(4.5 mL), NaN₃ (720 mg, 11.1 mmol) was added and the mixture was stirredat 50° C. until tlc indicated complete conversion of the cyclic sulfate.The solvent was removed under vacuum, the residue partitioned betweenether (160 mL) and water (4.5 mL), cooled to 0° C., whereupon 20% H₂ SO₄(13.5 mL) was dropwise added. The mixture was stirred vigorously at 23°C. for 37 h, the layers were separated, the organic layer washed withsat. NaHCO₃ -sol. and brine, dried over MgSO₄. After removal of thesolvent under vacuum, the residual oil (2.78 g, 97%) was purified bysilica gel column chromatography with hexane/ethyl acetate 9:1->5:1 togive(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VII-1) (1.79 g, 62%) as a colorlessoil. ¹ H-NMR (250 MHz, CDCl₃) □1.26 (3H, t, J=7.1 Hz), 1.81 (1H, t,J=3.1 Hz), 2.04-2.20 (3H, m), 2.25 (1H, dd, J=6.9, 2.9 Hz), 2.34 (1H,dd, J=7.7, 3.9 Hz), 3.80 (1H, bq, J=9 Hz), 4.12 (2H, q, J=7.1 Hz), 5.27(1H, d, J=12.2 Hz), 5.34 (1H, d, J=12.2 Hz), 7.36-7.40 (5H, m);MS[ISN]404 (M+OAc⁻); □_(D) ²⁰ -48.43° (c=1.09, CHCl₃).

EXAMPLE 6 (1S,2R,3R,5R,6S) -2-Amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-A)

A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1)(1.55 g, 4.49 mmol) in HOAc (20 mL) and H₂ O (5 mL) was hydrogenated inthe presence of Pd/C (100 mg, 10% Pd/C) at 23° C. for 18 h. The catalystwas removed by filtration, the filter cake washed with 50% aqueousacetic acid. After removal of the solvent in vacuum, the beige residuewas refluxed in 10% HCl (55 mL) for 4 h. The solution was cooled to 23°C., filtered, washed with water and evaporated to dryness. The remainingpale yellow solid was dissolved in EtOH (45 mL) and propylene oxide (24mL) and refluxed for 15 min, whereupon the amino acid precipiated. Aftercooling to 23° C., the product was filtered off, washed with ether anddried to give (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-A) (784 mg, 87%) as a whitesolid. ¹ H-NMR (250 MHz, D₂ O) □1.87 (1H, t, J=3.1 Hz), 2.15-2.26 (3H,m), 2.38 (1H, dd, J=13.0, 7.6 Hz), 3.97 (1H, dd,J=8.6,7.4 Hz);MS[ISP]202 (M+H⁺); mp>250° C.; □_(D) ²⁰ +7.41° (c=1.01, H₂ O).

EXAMPLE 7 (1S,2R,3R,5R,6S)-2-Amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VIII)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VII-1) (200 mg, 0.58 mmol) in MeOH(5.8 mL) and a few drops of chloroform at 0° C. was added NiCl₂.6 H₂ O(661 mg, 2.78 mmol) was dissolved in acetone (45 mL) and H₂ O (4.5 mL),NaN₃ (720 mg, 11.1 mmol) and stirred for 10 min at 0° C. Upon cautiousaddition of NaBH₄ (175 mg, 4.62 mmol) the reaction mixture turnedimmediately black, stirring was continued at 0° C. for 10 min and thenhydrolyzed with water and ether. After additional stirring for 10 min at0° C., the reaction mixture was extracted with ether, washed with brine(2×50 mL) and dried over Na₂ SO₄ and filtered through celite. Thesolvent was removed under vacuum, the residue was purified by silica gelcolumn chromatography with ethyl acetate/MeOH 95:5 (+0.6% Et₃ N) to give(1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VIII) (106 mg, 57%) as a yellow oil.¹ H-NMR (250 MHz, CDCl₃) □1.25 (3H, t, J=7.1 Hz), 1.75 (1H, t,J=3.5 Hz),1.97 (1H, m), 2.12 (1H, dd,J=7, 3.5 Hz), 2.14-2.28 (4H, m), 2.33 (1H,dd,J=12.5, 7 Hz), 3.65 (1H, dd, J=8, 7 Hz), 4.10 (2H, q, J=7.1 Hz), 5.22(1H, d, J=12.5 Hz), 5.27 (1H, d, J=12.5 Hz), 7.38 (5H, m); MS[ISP] 320(M+H⁺); □_(D) ²⁰ -0.56° (c=0.89, CHCl₃).

EXAMPLE 8(1S,2R,5R,6S)-2-Azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxulic acid2-benzyl ester 6-ethyl ester (IX-1)

To a solution of (1S,2R,3R,5R,6S)-2-Azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (960mg, 2.78 mmol) in DCM (18 mL) was added PCC (2.40 g, 50% on silica gel)at 0° C. and stirring was continued at 23° C. for 20 h. The reactionmixture was placed on a silica gel column and the product was elutedwith DCM to yield (1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(IX-1) (746 mg, 78%) as a white solid. ¹ H-NMR (250 MHz, CDCl₃) □1.27(3H, t, J=7.2 Hz), 1.62 (1H, t,J=3.4 Hz), 2.29 (1H, m), 2.44 (1H,dd,J=7.7, 3.1 Hz), 2.55 (1H, d, J=19.2 Hz), 2.98 (1H, dd, J=19.2, 5.6Hz), 4.13 (2H, q, J=7.2 Hz), 5.29 (2H, s), 7.36-7.40 (5H, m); MS[ISP]361(M+NH₄ ⁺); mp 46-48° C.; □_(D) ²⁰ +210.910 (c=1.07, CHCl₃).

EXAMPLE 9 (1S,2R,3S,5R,6S)-2-Azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1)

To a solution of(1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (IX-1) (100 mg, 0.29 mmol) in EtOH (1.7 mL)and THF (0.5 mL) was added NaBH₄ (22 mg, 0.58 mmol) at -50° C. andstirring was continued at -50° C. for 4 h. The reaction mixture waspoured on ice, acidified with 1 N HCl and extracted with ether. Afterwashing with sat. NaHCO₃ -sol., brine and drying over MgSO₄ the crudeproduct was purified by silica gel column chromatography withhexane/EtOAc 5:1 to give (1S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (X-1) (51 mg, 51%) as a colorless oil.¹ H-NMR (250 MHz, CDCl₃) □1.26 (3H, t, J=7.2 Hz), 2.03-2.18 (3H,m),2.31-2.48 (2H, m),2.53 (1H, t,J=4 Hz),4.13 (2H, q,J=7.2 Hz), 4.21(1H,bs), 5.26 (2H, s), 7.36-7.40 (5H, m); MS [EI]300 [(M--OEt)⁺ ];

EXAMPLE 10 (1S,2R,3S,5R,6S)-2-Amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-2)

A solution of (1S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1) (50 mg,0.145 mmol) in HOAc (4 mL) and H₂ O (1 mL) was hydrogenated in thepresence of Pd/C (11 mg, 10% Pd/C) at 23° C. for 23 h. The catalyst wasremoved by filtration, the filter cake washed with 50% aqueous aceticacid. After removal of the solvent in vacuum, the beige residue wasrefluxed in 10% HCl (6.75 mL) for 4 h. The solution was cooled to 23°C., filtered, washed with water and evaporated to dryness. The remainingpale yellow solid was dissolved in EtOH (5 mL) and propylene oxide (2mL) and refluxed for 15 min, whereupon the amino acid precipiated. Aftercooling to 23° C., the product was filtered off, washed with ether anddried to give(1S,2R,3S,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-2) (24 mg, 86%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □2.05(1H, d,J=15 Hz), 2.10-2.20 (2H, m), 2.12 (1H, m), 2.61 (1H, m), 4.20(1H, d, J=7.2 Hz); MS[ISP] 202 (M+H⁺); mp 208° C. (dec.); □_(D) ²⁰+27.52° (c=1.03, H₂ O).

EXAMPLE 11(1S,2R,3R,5R,6S)-2-Azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (XI)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VII) (845 mg, 2.45 mmol) in THF (21mL) and H₂ O (6 mL) was added LiOH.H₂ O (411 mg, 9.8 mmol) and themixture was stirred at 23° C. for 18 h. The benzyl alcohol was extractedwith ether, the aqueous layer acidified with 1 M KHSO₄ -sol., saturatedwith solid NaCl, extracted with EtOAc (4×50 mL) and dried over MgSO₄.After removal of the solvent under vacuum crude(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (XI) (581 mg, quant.) was obtained as white solid, sufficientlypure for further transformations. ¹ H-NMR (250 MHz, DMSO) □1.75 (1H, t,J=3.5 Hz), 1.84 (1H, m), 1.92-2.07 (2H, m), 2.15 (1H, dd, J=12.5, 7 Hz),3.87 (1H, btJ=7 Hz); MS[ISN] 226 [(M-H)-]; mp 124-128° C.; □_(D) ²⁰-61.48° (c=0.90, H₂ O).

EXAMPLE 12 (1S,2R,3R,5R,6S)-2-Azido-3-hvdroxy-bicyclo [3.10]hexane-2,6-dicarboxylic acid dimethyl ester (XII)

Crude (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (XI) (515 mg, 2.27 mmol) was dissolved inMeOH (20 mL) and stirred in the presence of conc. H₂ SO₄ (0.1 mL) at 23°C. for 7 d. The mixture was diluted with ether, washed with sat. NaHCO₃-sol., brine and dried over MgSO₄. After removal of the solvent invacuum, the residue was purified by silica gel column chromatographywith hexane/ethyl acetate 2:1 to give(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid dimethyl ester (XII) (500 mg, 86%) as a yellow oil. ¹ H-NMR (250MHz, CDCl₃) □1.84 (1H, t, J=3.1 Hz), 2.04-2.26 (2H, m),2.25 (1H,dd,J=6.9, 3.0 Hz), 2.37 (1H, dd,J=12.5, 7.8 Hz), 3.69 (3H, s), 3.83 (1H,bq, J=9 Hz), 3.90 (3H, s); MS [ISP] 273 (M+NH₄ ⁺); □_(D) ²⁰ -53.33°(c=1.11, CHCl₃).

EXAMPLE 13(1S,2R,5R,6S)-2-Azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylicdimethyl ester (XIII)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid dimethyl ester (XII) (239 mg, 0.94 mmol) in DCM (6 mL) was addedPCC (1.13 g, 2.62 mmol, 50% on silica gel) at 0° C. and the mixture wasstirred at 23° C. for 2 d. The PCC was removed by filtration through asilica gel column and the pure(1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylicdimethyl ester (XIII) was obtained by silica gel column chromatographywith hexane/EtOAc 2:1 as a white solid (152 mg, 64%). ¹ H-NMR (250 MHz,CDCl₃) □1.64 (1H, t,J=3.4 Hz), 2.34 (1H, ddd,J=7.7, 5.5, 3.2 Hz), 2.46(1H, dd,J=7.7, 3.1 Hz), 2.56 (1H, d,J=19.2 Hz), 3.06 (1H, dd, J=19.2,5.5 Hz), 3.71 (3H, s), 3.89 (3H, s); MS[EI] 222 [(M-OCH₃)⁺ ]; mp 62-65°C.;

EXAMPLE 14 (1S,2R,3R,5R.6S)-2-Azido-3-deutero-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester (XIV) and(1S,2R,3S,5R,6S)-2-Azido-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid dimethyl ester (XV)

A suspension of (1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic dimethyl ester (XIII) (123 mg, 0.486mmol) and anhydrous CeCl₃ (120 mg, 0.486 mmol) in MeOH (3.8 mL) wassonicated at 23° C. for 2 min and cooled to -78° C. NaBD₄ (21 mg, 0.486mmol) was added in one portion and the mixture was stirred at -50° C.for 30 min. The reaction was quenched by addition of HOAc (ca. 0.5 mL),warming up to 23° C. and stirring for 10 min. After dilution with etherand extraction with sat. NaHCO₃ -sol., brine and drying over MgSO₄ thecrude product was purified by silica gel column chromatography withhexane/EtOAc 2:1 to give(1S,2R,3S,5R,6S)-2-azido-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester (XV) (47 mg, 38%,less polar product) and(1S,2R,3R,5R,6S)-2-azido-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid dimethyl ester (XIV) (15 mg, 12%, more polar product) both as acolorless oil. (XV): ¹ H-NMR (250 MHz, CDCl₃) □2.04-2.11 (2H, m), 2.20(1H, bs), 2.36 (1H, dd, J=6.6, 3.0 Hz), 2.45 (1H, dd, J=13, 5.5 Hz),2.56 (1H, t, J=3.1 Hz), 3.70 (3H, s), 3.85 (3H, s); MS[ISP] 274 (M+NH₄⁺); (XIV): ¹ H-NMR (250 MHz, CDCl₃) □1.84 (1H, t, J=3.5 Hz), 2.07 (1H,dd, J=6.5, 3.5 Hz), 2.16 (1H, dd, J=12.5, 5.5 Hz), 2.27 (1H,dd,J=6.5,3.5 Hz), 2.33 (1H, s), 2.37 (1H, d,J=12.5Hz),3.69 (3H, s), 3.90(3H, s); MS[ISP] 274 (M+NH₄ ⁺);

EXAMPLE 15 (1S,2R,3R,5R,6S)-2-Amino-3-deutero-3-hydroxy-bicyclo[3.10]hexane-2,6-dicarboxylic acid (I-3)

A solution of (1S,2R,3R,5R,6S)-2-azido-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester (XIV) (15 mg, 0.058mmol) in HOAc (1 mL) and H₂ O (0.25 mL) was hydrogenated in the presenceof Pd/C (5 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed byfiltration and the catalyst washed with water. After removal of thesolvent in vacuum, the beige residue was refluxed in 10% HCl (2 mL) for4 h. The solution was cooled to 23° C.. and evaporated to dryness. Theremaining pale yellow solid was dissolved in EtOH (2 mL) and propyleneoxide (0.5 mL) and refluxed for 15 min, whereupon the amino acidprecipiated as white fluffy material. After cooling to 23° C., theproduct was filtered off, washed with ether, taken up in water andlyophilized to give(1S,2R,3R,5R,6S)-2-amino-3-deutero-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-3) (9 mg, 76%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □1.45(1H, t,J=3.1 Hz), 1.71 (1H, m), 1.79 (1H, dd, J=7, 3.0 Hz), 1.94 (1H,dd,J=12.5, 5 Hz), 2.17 (1H, d, J=12.6 Hz); MS[ISN] 201 [(M--H)³¹ ]mp>250° C.; □_(D) ²⁰ 0.94° (c=0.32, H₂ O).

EXAMPLE 16 (1S,2R,3S,5R,6S)-2-Amino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-4)

A solution of (1S,2R,3S,5R,6S)-2-azido-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester (XV) (47 mg, 0.183mmol) in HOAc (2 mL) and H₂ O (0.5 mL) was hydrogenated in the presenceof Pd/C (9 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed byfiltration and the catalyst washed with water. After removal of thesolvent in vacuum, the beige residue was refluxed in 10% HCl (3 mL) for4 h. The solution was cooled to 23° C. and evaporated to dryness. Theremaining pale yellow solid was dissolved in EtOH (3 mL) and propyleneoxide (1.5 mL) and refluxed for 15 min, whereupon the amino acidprecipiated as white fluffy material. After cooling to 23° C., theproduct was filtered off, washed with ether, taken up in water andlyophilized to give(1S,2R,3S,5R,6S)-2-amino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-4) (32 mg, 86%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □2.05(1H, d, J=15 Hz), 2.14 (2H, m), 2.23 (1H, dd, J=7,3.5 Hz), 2.60 (1H, dd.J=15, 5 Hz); MS[ISN] 201 [(M-H)⁻ ]; mp>250° C.; □_(D) ²⁰ +31.26°(c=0.12, H₂ O).

EXAMPLE 17(1S,2R,5R,6S)-2-Acetylamino-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XVI)

A solution of(1S,2R,5R,6S)-2-Azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (IX) (974 mg, 2.84 mmol) in thioacetic acid(6.5 mL) was stirred at 70° C. for 2 d. The reaction mixture wasconcentrated in vacuum and subjected to silica gel column chromatographywith hexane/ethyl acetate 3:2->1:1 to yield(1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XVI) (726 mg, 71%) as a pink oil. ¹H-NMR (250 MHz, CDCl₃) □1.25 (3H, t, 1=7.1 Hz), 1.63 (1H, t, J=3.5 Hz),2.05 (3H, s), 2.32 (1H, ddd,J=7, 6,3.5 Hz), 2.54 (1H, d,J=19 Hz), 2.90(1H, dd,J=19, 6 Hz), 3.06 (1H, dd, J=7, 3.5 Hz), 4.12 (2H, m), 5.16 (1H,d, J=12 Hz), 5.25 (1H, d, J=12 Hz), 7.24-7.35 (5H, m); MS[ISP] 360(M+H⁺); □_(D) ²⁰ +44.33° (c=0.97, CHCl₃).

EXAMPLE 18(1S,2R,3R,5R,6S)-2-Acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XVII) and(1S,2R,3S,5R,6S)-2-Acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic 2-benzyl ester 6-ethyl ester (XVIII)

To a solution of (1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0]hexane-2,6-dicarboxylic 2-benzyl ester 6-ethyl ester (XVI) (77 mg, 0.214mmol) in EtOH (2 mL) and THF (1 mL) was added LiBH₄ (5 mg, 0.23 mmol) at-50° C. and the mixture was stirred at -50° C. for 45 min. The reactionwas quenched by addition of 1 N HCl (ca. 0.5 mL), warming up to 23° C.and stirring for 10 min. After dilution with ethyl acetate andextraction with sat. NaHCO₃ -sol., brine and drying over MgSO₄ the crudeproduct was purified by silica gel column chromatography withtoluene/acetone 3:1 to give(1S,2R,3R,5R,6S)-2-acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XVII) (33 mg, 43%, less polarproduct) as a colorless oil and(1S,2R,3S,5R,6S)-2-acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XVIII) (35 mg, 45%, more polarproduct) as a white solid. (XVII): ¹ H-NMR (250 MHz, CDCl₃) □1.26 (3H,t, J=7.2 Hz), 1.76 (1H, t, J=3.5 Hz), 2.07 (1H, m), 2.10 (3H, s), 2.16(1H, dd, J=6.1, 3.0 Hz), 2.30-2.41 (3H, m), 3.97-4.13 (3H, m), 5.24 (2H,bs), 6.19 (1H, bs), 7.26-7.38 (5H, m); MS[ISP] 362 (M+H⁺); □_(D) ²⁰-11.24° (c=1.18, CHCl₃). (XVIII): ¹ H-NMR (250 MHz, CDCl₃) □1.25 (3H, t,J=7.1 Hz), 1.98 (1H, m), 2.05-2.11 (1H, m),2.06 (3H, s), 2.18(1H,t,J=3.5 Hz), 2.27-2.41 (2H, m), 2.59 (1H, ddd,J=13, 7, 5 Hz), 4.12(2H, m), 4.68 (1H, dd, J=7, 5 Hz), 5.17 (2H, s), 6.30 (1H, bs),7.26-7.40 (5H, m); MS[ISP] 362 (M+H⁺); mp 145-147° C.; □_(D) ²⁰ +42.44°(c=1.01, CHCl₃).

EXAMPLE 19 (1S,2R,3R,5R,6S)-2-Acetylamino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XIX)and(1S,2R,3S,5R,6S)-2-Acetylamino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic2-benzyl ester 6-ethyl ester (XX)

To a solution of (1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0]hexane-2,6-dicarboxylic 2-benzyl ester 6-ethyl ester (XVI) (105 mg,0.292 mmol) in EtOH (1.9 mL) and THF (1.0 mL) was added NaBD₄ (24.5 mg,0.584 mmol) at -50° C. and the mixture was stirred at -50° C. for 90min. The reaction was quenched by addition of HOAc (ca. 0.5 mL), warmingup to 23° C. and stirring for 10 min. After dilution with ethyl acetate,1 N HCl was added, followed by washings with sat. NaHCO₃ -sol., brineand drying over MgSO₄. After removal of the solvent in vacuum the crudeproduct was purified by silica gel column chromatography withtoluene/acetone 3:1 to give(1S,2R,3R,5R,6S)-2-acetylamino-3-deutero-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XIX) (45 mg,43%, less polar product) as a colorless oil and(1S,2R,3S,5R,6S)-2-acetylamino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XX)(50 mg, 47%, more polar product) as a white solid. (XIX): ¹ H-NMR (250MHz, CDCl₃) □1.26 (3H, t, J=7.2 Hz), 1.98 (1H, m), 1.74 (1H, t, J=3.5Hz), 2.04-2.10 (1H, m), 2.09 (3H, s), 2.17 (1H, dd, J=7, 2.9 Hz),2.35-2.40 (3H, m), 4.10 (2H, m), 5.24 (2H, s), 6.33 (1H, bs), 7.26-7.37(5H, m); MS[ISP] 363 (M+H⁺); (XX): ¹ H-NMR (250 MHz, CDCl₃) □1.24 (3H,t, J=7.1 Hz), 1.97 (1H, ddd, J=8,6.5,3 Hz), 2.04 (3H, s), 2.06 (1H, dd,J=13.5, 3.7 Hz), 2.17 (1H, t, J=3.1 Hz), 2.32 (1H, dd, J=6.6, 3.0 Hz),2.56 (1H, dd, J=13.5, 5 Hz), 2.58 (1H, s), 4.09 (2H, m), 5.23 (2H, s),6.42 (1H, bs), 7.28-7.40 (5H, m); MS[ISP] 363 (M+H³⁰ );

EXAMPLE 20 (1S,2R,3R,5R,6S)-2-Acetylamino-3-hvdroxy-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXI)and(1S,2R,3S,5R,6S)-2-Acetylamino-3-hydroxy-3-tritiobicylo[3.1.0]hexane-2,6-dicarboxylic2-benzyl ester 6-ethyl ester (XXII)

Radiochemical samples were counted in a wallac WinSpectral 1414 LiquidScintillation Counter using OptiPhase `HiSafe`3 as scintillationcocktail.

n-Butyl lithium (200 μL, 0.312 mmol, 1.56 M in n-hexane) andN,N,N',N'-tetramethylethylenediamine (52 μL, 0.347 mmol) weretransferred into a 7.5 mL-two-necked-flask mounted to the tritiationapparatus under argon. The stopcock of the side neck was closed and themixture was stirred under an atmosphere of tritium gas for 2 h 43 min,while the tritium gas pressure dropped from 646 mbar to 559 mbar. Excesstritium gas was reabsorbed onto the uranium bed and the volatilecomponents were lyophilized off. The residue was dried at 10⁻³ mbar forabout 5 min. The flask was filled with dry nitrogen and the LiT wassuspended in THF (250 μL), which was added by syringe through thesilicon septum (Hamilton # 76005) of the side neck. Then trimethylborate(35 μL, 0.314 mmol) was added and the mixture was stirred for 10 min.The two-necked-flask was disconnected from the tritiation apparatus andequipped with a balloon filled with argon.(1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic2-benzyl ester 6-ethyl ester (XVI) (118.7 mg, 0.33 mmol) in THF (250 μL)was added at -60° C. After stirring for 30 min the reaction was quenchedby adding 1 N HCl (0.31 mL). The reaction mixture was partitionedbetween EtOAc and H₂ O. The organic phase was washed with saline (1×)and dried over Na₂ SO₄. The total ³ H-activity of the crude product was5.18 Ci. Column chromatography using 15 g of Lichroprep Si60 25-40 μm(Merck Art.1.09390) with toluene/acetone 5:1 afforded 1.152 Ci of(1S,2R,3R,5R,6S)-2-acetylamino-3-hydroxy-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXI) with 99% radiochemical purityaccording to TLC (toluene/acetone 3:1). The specific activity was 23.9Ci/mmol according to mass spectrometry. In addition about 2 Ci of(1S,2R,3S,5R,6S)-2-acetylamino-3-hydroxy-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXII)were isolated.

EXAMPLE 21 (1S,2R,3R,5R,6S) -2-Amino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-3)

(1S,2R,3R,5R,6S)-2-Acetylamino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XIX)(15 mg, 0.058 mmol) was refluxed in 10% HCl (3.7 mL) for 6 h. Thesolution was cooled to 23° C. and evaporated to dryness. The remainingpale yellow solid was dissolved in EtOH (3 mL) and propylene oxide (1.6mL) and refluxed for 15 min, whereupon the amino acid precipiated aswhite fluffy material. After cooling to 23° C., the product was filteredoff, washed with ether, taken up in water and lyophilized to give(1S,2R,3R,5R,6S)-2-amino-3-deutero-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-3) (12 mg, 71%) as a white solid. Analytical data the same as inexample 15.

EXAMPLE 22 (1S,2R,3R,5R,6S)-2-Amino-3-hydroxU-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-5)

(1S,2R,3R,5R,6S)-2-Acetylamino-3-hydroxy-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXI)(576 mCi) was refluxed in 10% HCl (5 mL) for 6 h. The reaction mixturewas diluted with H₂ O (5 mL) and applied onto a Dowex 50WX8 100-200 meshcation exchange column (7.5×70 mm). The column was rinsed with H₂ O (20mL). Elution with 2 N NH₄ OH (20 mL) afforded(1S,2R,3R,5R,6S)-2-amino-3-hydroxy-3-tritio-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-5) (280 mCi). The radiochemicalpurity was 91.7% according to TLC (n-BuOH/HOAc/H₂ O 3:1:1). The crudeproduct (56 mCi) was purified by HPLC on a μBondapak C18 column (3.9×300mm) using H₂ O/acetonitrile 95:5 (v/v) as mobile phase with a flow rateof 0.8 mL/min and UV-detection at 220 nm. The total ³ H-activityobtained was 43 mCi and the radiochemical purity was 98.1% according toTLC (n-BuOH/HOAc/H₂ O 3:1:1).

EXAMPLE 23 (1S,2R,3R,5R,6S)-2-Azido-3-methoxv-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXIII-1)

A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1)(345 mg, 1.0 mmol), 2,6-di-tert.-butylpyridine (1.35 mL, 6.0 mmol) andmethyl triflate (0.55 mL, 5.0 mmol) in DCM (2 mL) was stirred at 23° C.for 4 d. The reaction mixture was poured on ice, acidified with 1 N HCland extracted with ether. After washing with sat. NaHCO₃ -sol., brineand drying over MgSO₄ the crude product was purified by silica gelcolumn chromatography with hexane/EtOAc 4:1 to give(1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-1) (226 mg, 63%) as a yellowoil. ¹ H-NMR (250 MHz, CDC1₃) □1.26 (3H, t, J=7.1 Hz), 1.77 (1H, t,J=3.5 Hz), 2.05-2.18 (2H, m), 2.25 (1H, dd, J=7, 3.5 Hz), 2.34 (1H, dd,J=12, 7 Hz), 3.28 (3H, s), 3.42 (1H, bt,J=8 Hz), 4.12 (2H, q, J=7.1 Hz),5.25 (1H, d,J=12 Hz), 5.34 (1H, d, J=12 Hz), 7.30-7.40 (5H, m); MS [EI]258 [ (M--CO₂ Et-N₂)⁺ ]; □_(D) ²⁰ -48.02° (c=1.11, CHCl₃).

EXAMPLE 24(1S,2R,3R,5R,6S)-3-Allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-2)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VII) (200 mg, 0.58 mmol) and allyl2,2,2-trichloroacetimidate (0.18 mL, 1.16 mmol) in cyclohexane (0.7 mL)was added TfOH (29 □L), whereupon the solution became hot and stirringwas continued at 23° C. for 1 h. The reaction mixture was poured on ice,diluted with ether, washed with sat. NaHCO₃ -sol., brine and dried overMgSO₄. The crude product was purified by silica gel columnchromatography with hexane/EtOAc 4:1 to give(1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXIII-2) (31 mg, 14%) as a yellow oil. ¹ H-NMR (250 MHz, CDCl₃) □1.26(3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.03-2.26 (3H, m), 2.32 (1H,dd, J=12, 7 Hz), 3.58 (1H, dd, J=9, 7 Hz), 3.92 (1H, m), 4.02 (1H, m),4.13 (2H, q, J=7.1 Hz), 5.10-5.22 (2H, m), 5.25 (1H, d,J=12 Hz), 5.34(1H, d,J=12 Hz), 5.75 (1H, m), 7.30-7.42 (5H, m);MS[EI] 284 [(M-CO₂Et-N₂)⁺ ]; □_(D) ²⁰ 17.85° (c=0.50, CHCl₃).

EXAMPLE 25(1S,2R,3R,5R,6S)-2-Azido-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-3)

To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII)(305 mg, 0.88 mmol) and benzyl 2,2,2-trichloroacetimidate (0.2 mL, 1.06mmol) in cyclohexane (2.4 mL) and DCM (1.2 mL) was added TfOH (0.05 mL),whereupon the solution became hot and stirring was continued at 23° C.for 5 h. The reaction mixture was poured on ice, diluted with ether,washed with sat. NaHCO₃ -sol., brine and dried over MgSO₄. The crudeproduct was purified by silica gel column chromatography withhexane/EtOAc 4:1 to give(1S,2R,3R,5R,6S)-2-azido-3-benzyloxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-3) (102 mg, 27%) as a yellowoil. ¹ H-NMR (250 MHz, CDCl₃) □1.25 (3H, t, J=7.1 Hz), 1.75 (1H, t,J=3.5 Hz), 2.06 (1H, m), 2.17-2.31 (3H, m), 3.60 (1H, bt, J=8 Hz), 4.12(2H, q, j=7.1 Hz), 4.42 (1H, d, J=12 Hz), 4.57 (1H, d,J=12 Hz), 5.23(1H, d,J=12 Hz), 5.34 (1H, d,J=12 Hz), 7.15-7.42 (10H, m); MS[ISP] 408[(M+H-N₂)⁺ ]; □_(D) ²⁰ +2.03 ° (c=0.99, CHCl₃).

EXAMPLE 26(1S,2R,3R,5R,6S)-3-Allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIV-2)

To a solution of(1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-2) (101 mg, 0.262 mmol) in THF(3.9 mL) and H₂ O (0.4 mL) was added Me₃ P (0.29 mL, 0.29 mmol, 1 M sol.in THF) and stirring was continued at 23° C. for 3 h. The reactionmixture was diluted with ether, washed with sat. NaHCO₃ -sol., brine anddried over Na₂ SO₄. The crude product was purified by silica gel columnchromatography with hexane/EtOAc 1:1 (+small amount of Et₃ N) to give(1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIV-2) (47 mg, 50%) as a light brownoil. ¹ H-NMR (250 MHz, CDCl₃) □1.24 (3H, t, J=7.1 Hz), 1.76 (1H, t,J=3.5 Hz), 1.93 (2H, bs), 1.99 (1H, m), 2.07-2.18 (2H, m), 2.31 (1H, dd,J=12.5, 7 Hz), 3.45 (1H, bt, J=8 Hz), 3.93 (2H, bd,J=6 Hz), 4.12 (2H, q,J=7.1 Hz), 5.10-5.35 (4H, m), 5.78 (1H, m), 7.28-7.38 (5H, m); MS[ISP]360 [(M+H)⁺ ]; □_(D) ²⁰ -10.67° (c=1.00, CHCl₃).

EXAMPLE 27 (1S,2R,3R,5R,6S) -2-Amino-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzvl ester 6-ethyl ester(XXIV-3)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-3) (120 mg, 0.276 mmol) in THF(4 mL) and H₂ O (0.4 mL) was added Me₃ P (0.30 mL, 0.30 mmol, 1 M sol.in THF) and stirring was continued at 23° C. for 4 h. The reactionmixture was diluted with ether, washed with sat. NaHCO₃ -sol., brine anddried over Na₂ SO₄. The crude product was purified by silica gel columnchromatography with hexane/EtOAc 1:1 (+small amount of Et₃ N) to give(1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXIV-3) (58 mg, 51%) as a yellow oil. ¹ H-NMR (250 MHz, CDCI₃) □1.23(3H, t, J=7.1 Hz), 1.72 (1H, t, J=3.5 Hz), 1.93 (2H, bs), 2.00 (1H, m),2.10 (1H, dd, J=7, 3.5 Hz), 2.19 (1H, m), 2.27 (1H, dd,J=12,7 Hz), 3.46(1H, dd,J=8, 7 Hz), 4.10 (2H, q,J=7.1 Hz), 4.47 (2H, s),5.20 (1H,d,J=12Hz), 5.30 (1H, d,J=12 Hz), 7.18-7.42 (10H,m);MS[ISP] 410 [(M+H)⁺ ];□_(D) ²⁰ +3.54° (c=0.90, CHCl₃).

EXAMPLE 28 (1S,2R,3R,5R,6S)-2-Amino-3-methoxy-bicylo[3.1.0]hexane-2,6-dicarboxylic acid (I-7)

A solution of(1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXIII-1) (214 mg, 0.56 mmol) in HOAc(8 mL) and H₂ O (2 mL) was hydrogenated in the presence of Pd/C (35 mg,10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration,the filter cake washed with 50% aqueous acetic acid. After removal ofthe solvent in vacuum, the beige residue was refluxed in 10% HCl (15 mL)for 4 h. The solution was cooled to 23° C., filtered, washed with waterand evaporated to dryness. The remaining pale yellow solid was dissolvedin EtOH (10 mL) and propylene oxide (5.6 mL) and refluxed for 15 min,whereupon the amino acid precipiated. After cooling to 23° C., theproduct was filtered off, washed with ether and dried to give(1S,2R,3R,5R,6S)-2-amino-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-7) (100 mg 74%) as a white solid.¹ H-NMR (250 MHz, D₂ O) □1.86 (1H, t, J=3.5 Hz), 2.04-2.23 (3H, m), 2.50(1H, dd, J=12, 7 Hz), 3.29 (3H, s), 3.62 (1H, bt,J=8 Hz); MS[ISN] 214[(M-H)⁻ ]; mp>250° C.; □_(D) ²⁰ -13.84° (c=1.01, H₂ O).

EXAMPLE 29

cl(1S,2R,3R,5R,6S)-2-Amino-3-propoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-8)

A solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXIII-2) (28 mg, 0.073 mmol) in HOAc (0.75 mL) and H₂ O (0.25 mL) washydrogenated in the presence of Pd/C (3 mg, 10% Pd/C) at 23° C. for 18h. The catalyst was removed by filtration, the filter cake washed with50% aqueous ethanol. After removal of the solvent in vacuum, the beigeresidue was refluxed in 10% HCl (1.25 mL) for 4 h. The solution wascooled to 23° C. and evaporated to dryness. The remaining pale yellowsolid was dissolved in EtOH (1 mL) and propylene oxide (0.5 mL) andrefluxed for 10 min, whereupon the amino acid precipiated. After coolingto 23° C., the product was filtered off, washed with ether and dried togive (1S,2R,3R,5R,6S)-2-amino-3-propoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-8) (13 mg, 72%) as a white solid.¹ H-NMR (250 MHz, D₂ O) □0.81 (1H, t, J=7.5 Hz), 1.48 (2H, m), 1.84 (1H,m), 2.16 (3H, m), 2.26 (1H, dd,J=12,7 Hz), 3.43 (2H, m), 3.73(1H,bt,J=8Hz); MS[ISN] 242 [(M-H)⁻ ]; mp >2500 C; □_(D) ²⁰ 3.72°(c=0.19, H₂ O).

EXAMPLE 30 (1S.2R.3R.5R.6S)-3-Allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-9)

A solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXIV-2) (47 mg, 0.131 mmol) and LiOH.H₂ O (15 mg, 0.357 mmol) in THF (4mL), H₂ O (2 mL) and MeOH (0.4 mL) was stirred at 23° C. for 36 h. Thesolution was acidified with conc. HCl and evaporated to dryness. Theremaining pale yellow solid was suspended in EtOH, filtered, washed withmore EtOH and the filtrate was evaporated to dryness. The residue wasdissolved in EtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3min, whereupon the amino acid precipiated. After cooling to 23° C., theproduct was filtered off, washed with ether and dried to give(1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-9) (19 mg, 59%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □1.48(1H, t, J=3.5 Hz), 1.78 (2H, m), 1.98 (1H, ddd, J=12.5, 8,3.5 Hz), 2.27(1H, dd, J=12.5, 7 Hz), 3.44 (1H, bt, J=7.5 Hz), 3.97 (2H, m), 5.13-5.26(2H, m), 5.82 (1H, ddt, J=18, 11, 6 Hz); MS[ISN] 240 [(M-H)⁻ ]; mp>250°C.; Ξ_(D) ²⁰ -10.62° (c=0.40, H₂ O).

EXAMPLE 31 (1S,2R,3R,5R,6S)-2-Amino-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-10)

A solution of (1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-3) (50mg, 0.122 mmol) and LiOH.H₂ O (13 mg, 0.30 mmol) in THF (4 mL), H₂ O (2mL) and MeOH (0.4 mL) was stirred at 23° C. for 36 h. The solution wasacidified with conc. HCl and evaporated to dryness. The remaining paleyellow solid was suspended in EtOH, filtered, washed with more EtOH andthe filtrate was evaporated to dryness. The residue was dissolved inEtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3 min, whereuponthe amino acid precipiated. After cooling to 23° C., the product wasfiltered off, washed with ether and dried to give(1S,2R,3R,5R,6S)-2-amino-3-benzyloxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid (I-10) (26 mg, 72%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □1.57(1H, t, J=3.5 Hz), 1.97 (2H, m), 2.13 (1H, ddd, J=12.5, 8,3.5 Hz), 2.35(1H, dd, J=12.5, 7 Hz), 3.73 (1H, dd, J=8, 7 Hz), 4.51 (2H, s), 7.36(5H, bm); MS[ISN] 290 [(M-H)⁻ ]; mp>250° C.; □_(D) ²⁰ -5.69° (c=0.25, H₂O).

EXAMPLE 32(1S,2R,3R.5R,6S)-2-Azido-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXV)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (VUI-1) (518 mg, 1.5 mmol) andpyridine (0.36 mL, 4.5 mmol) in DCM (19 mL) at -78° C. was addedtrifluoromethanesulfonic anhydride (0.37 mL, 2.25 mmol) in DCM (1.4 mL)and the mixture was allowed to reach 0° C. The reaction mixture wasdiluted with ether, poured on ice, extracted with sat. CuSO₄ -sol. andbrine, followed by drying over Na₂ SO₄. After removal of the solvent invacuum, the crude product was purified by silica gel columnchromatography with hexane/EtOAc 4:1 to give(1S,2R,3R,5R,6S)-2-azido-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXV) (574 mg, 86%) as a colorlessoil. ¹ H-NMR (250 MHz, CDCl₃) □ 1.27 (3H, t, J=7.1 Hz), 1.84 (1H,t,J=3.5 Hz), 2.17 (1H, m), 2.34 (1H, dd,J=7, 3.5 Hz), 2.53 (2H, m), 4.15(2H, q,J=7.1 Hz),4.58 (1H,bt,J=8Hz), 5.26 (1H, d,J=2 Hz), 5.41 (1H,d,J=12 Hz), 7.39 (5H, s); MS[ISP] 495 (M+NH₄ ⁺); □_(D) ²⁰ -17.30°(c=1.09, CHCl₃).

EXAMPLE 33(1S,2R,5R,6S)-2-Azido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVI-1)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXV) (1.36 g, 2.85 mmol) in THF (5.7mL) was added DBU (0.47 mL, 3.13 mmol) and the mixture was stirred at-50° C. for 3 h. After dilution with ethyl acetate, the solution waswashed with 1 N HCl-sol., sat. NaHCO₃ -sol. and brine, followed bydrying over MgSO₄. Removal of the solvent in vacuum left the crude(1S,2R,5R,6S)-2-azido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVI) (566 mg, 61%) as a brownish oil,sufficiently pure for further transformations. ¹ H-NMR (250 MHz, CDCl₃)□1.27 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.59 (1H, dt, J=7, 3.5Hz), 2.67 (1H, ddd, J=7, 3.5, 2 Hz), 4.14 (2H, q,J=7.1 Hz), 5.27 (2H,s), 5.53 (1H, d, J=5.5 Hz), 6.25 (1H, dd, J=5.5, 2Hz), 7.37 (5H, s);MS[ISP] 345 (M+NH₄ ⁺); □_(D) ²⁰ -7183.54° (c=1.08, CHCl₃).

EXAMPLE 34(1S,2R,5R,6S)-2-Amino-bicyclof[3.1.01]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVII)

To a solution of (1S,2R,5R,6S)-2-azido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester(XXVI) (66 mg, 0.202 mmol) in THF (4.5 mL) and H₂ O (0.5 mL) was addedpolymer supported PPh₃ (130 mg, 0.404 mmol, 3.1 mmollg) and the mixturewas stirred at 60° C. for 19 h. The resin was filtered off and washedwith DCM. Removal of the solvent in vacuum left a yellow oil which waspurified by silica gel column chromatography with hexane/ethyl acetate1:3 to give (1S,2R,5R,6S) -2-amino-bicyclo [3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVII) (19mg, 31%) as a colorless oil. ¹ H-NMR (250 MHz, CDCl₃) □1.25 (3H, t,J=7.2 Hz), 1.55 (1H, t, J=2.9 Hz), 1.78 (2H, bs), 2.53 (2H, m),4.12 (2H,q,J=7.2 Hz), 5.21 (2H, s), 5.37 (1H, d,J=5.3 Hz), 6.07 (1H, dd,J=5.3, 2Hz), 7.35 (5H, s); MS[ISP] 302 (M+H⁺); □_(D) ²⁰ -322.98 (c=0.77, CHCl₃).

EXAMPLE 35 (1S,2R,5R,6S)-2-Amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid (I-10)

A solution of(1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVII) (19 mg, 0.063 mmol) and LiOH.H₂ O(8 mg, 0.19 mmol) in THF (2 mL), H₂ O (0.5 mL) and MeOH (0.2 mL) wasstirred at 23° C. for 10 h. The solution was acidified with conc. HCland evaporated to dryness. The remaining pale yellow solid was suspendedin EtOH, filtered, washed with more EtOH and the filtrate was evaporatedto dryness. The residue was dissolved in EtOH (1 mL) and propylene oxide(1 mL) and refluxed for 3 min, whereupon the amino acid precipiated.After cooling to 23° C., the product was filtered off, washed with etherand dried to give(1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid(I-10) (11 mg, 95%) as a white solid. ¹ H-NMR (250 MHz, D₂ O) □1.59 (1H,t,J=3 Hz), 2.32 (1H, m), 2.60 (1H, m), 5.44 (1H, d, J=5.5 Hz), 6.37 (1H,dd,J=5.5, 2 Hz); MS[ISN] 182 [(M-H)⁻ ]; mp>250° C.;

EXAMPLE 36 (1S,2R.5R,6S)-2-Amino-3,4-ditritio-bicvclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid (I-B)

Radiochemical samples were counted in a Berthold BF 5020 liquidscintillation counter using Safetron-150 as scintillation cocktail.

A solution of(1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid(I-10) (4.4 mg, 20 μmol) in EtOH (0.5 mL) and H₂ O (0.5 mL) was stirredin the presence of Pd/C (1 mg, 10% Pd on activated carbon) under anatmosphere of tritium gas for 1 h at 23° C. Excess tritium gas wasreabsorbed onto the uranium bed and the solvent was lyophilized off. Theresidue was thrice taken up in EtOH (0.5 mL) and H₂ O (0.5 mL), stirredbriefly and lyophilized to ensure complete removal of labile boundtritium. The residue was suspended in EtOH/H₂ O 1:1 and the catalyst wasremoved by filtration through a 0.45 μm Millex-HA cartridge. The totalactivity of the crude product was 718 mCi. The radiochemical purity was94.3% according to TLC [n-BuOH/HOAc/H₂ O 3:1:1]. Part of the crudeproduct (72 mCi) was purified by HPLC on a Nucleosil C8 column (5 μm,4×250 mm), using a 25 mM KH₂ PO₄ -sol. as mobile phase with a flow rateof 0.5 mL/min and UV-detection at 220 nm. In order to remove the buffersalt from the mobile phase the sample was applied onto a SP-Sephadexcation exchange column (10×115 mm, H⁺ -form). The column was rinsed withH₂ O (20 mL) and the compound was eluted with 2 N NH₄ OH while 5min-fractions were collected. Fractions 6 and 7 containing ³ H-activitywere pooled and the volume was reduced to ca. 2 mL by evaporation at ca.25 mbar. The sample was diluted to 20 ml with EtOH/H₂ O 1:1. The totalactivity was 37.5 mCi. The radiochemical purity was 98.3% according toTLC [n-BuOH/HOAc/H₂ O 3:1:1]. The specific activity determined by massspectrometry was 35 Ci/mmol.

EXAMPLE 37(1S,2R,3S,5R,6S)-2,3-Diazido-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVIII-1)

To a solution of(1S,2R,3R,5R,6S)-2-azido-3-trifluoromethanesulfonyloxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXV) (200 mg, 0.48 mmol) in DMF (0.8mL) was added NaN₃ (187 mg, 2.88 mmol) and the mixture was stirred at80° C. for 1 h. After cooling to 23° C., the reaction was poured ontoice, extracted with ethyl acetate, washed with brine and dried overMgSO₄. Removal of the solvent in vacuum left the crude(1S,2R,3S,5R,6S)-2-diazido-bicyclo [3.1.0] hex-3-ene-2,6-dicarboxylicacid 2-benzyl ester 6-ethyl ester (XXVIII), contaminated with ca. 12% of(1S,2R,5R,6S)-2-azido-bicyclo [3.1.0]hex3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVI), which was removed by reacting themixture with OSO₄ (3 drops of a 2.5% sol. in t-BuOH), NMO (18 mg, 0.162mmol) in acetone (1.5 mL) and H₂ O (3 mL) at 23° C. for 24 h. Afterquenching with sodium sulfite (ca. 150 mg ) the reaction was poured ontoice, extracted with EtOAc (3×50 mL) and dried over MgSO₄. After removalof the solvent in vacuum, the residue was purified by silica gel columnchromatography with hexane/ethyl acetate 4:1 to give(1S,2R,3S,5R,6S)-2-diazido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVIII) (81 mg, 49%) as a colorless oil. ¹H-NMR (250 MHz, CDCl₃) □1.27 (3H, t, J=7.2 Hz), 1.97 (1H, m), 2.02 (1H,d, J=15.2 Hz), 2.32-2.40 (2H, m), 2.48 (1H, ddd, J=15, 7.5, 5 Hz), 4.14(2H, q, J=7.2 Hz), 4.20 (1H, d, J=7.4 Hz), 5.28 (2H, s), 7.39 (5H, s);MS[ISP] 388 (M+NH₄ +); □_(D) ²⁰ 56.71° (c=1.11, CHCl₃).

EXAMPLE 38 (1S,2R,3S,5R,6S)-2,3-Diamino-bicylo[3.1.0]hexane-2,6-dicarboxylic acid (I-12)

A solution of(1S,2R,3S,5R,6S)-2-diazido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid2-benzyl ester 6-ethyl ester (XXVIII-1) (45 mg, 0.122 mmol) in HOAc (3.8mL) and H₂ O (0.95 mL) was hydrogenated in the presence of Pd/C (12 mg,10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration,the filter cake washed with water. After removal of the solvent invacuum, the brown residue was refluxed in 10% HCl (8.9 mL) for 4 h. Thesolution was cooled to 23° C., filtered, washed with water andevaporated to dryness. The remaining beige solid was dissolved in EtOH(7.1 mL) and propylene oxide (3.8 mL) and refluxed for 15 min, whereuponthe amino acid precipiated. After cooling to 23° C., the product wasfiltered off, washed with ether and dried to give(1S,2R,3S,5R,6S)-2,3-diamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid(I-12) (19 mg, 79%) as a beige solid. ¹ H-NMR (250 MHz, D₂ O) □1.80 (1H,t, J=3 Hz), 2.00 (1H, dd, I=15, 5 Hz), 2.10 (1H, m), 2.15 (1H, dd, I=5,3Hz), 2.82 (1H, ddd, J=15, 10, 5 Hz), 4.07 (1H, dd, J=10, 5 Hz);MS[ISN]199 [(M-H)⁻ ]; mp>250° C.; □_(D) ²⁰ +9.50° (c=0.29, H₂ O).

What is claimed is:
 1. A process for the preparation of a compound offormula ##STR35## wherein R¹ is hydroxy, lower alkoxy, lower alkenyloxy,benzyloxy, hydrogen, deuterium or tritium,R¹¹ is hydrogen, deuterium,tritium, hydroxy or amino, and R² is hydrogen or tritium, or R¹ and R²form a bond,which process comprises: a) reacting a compound of formula##STR36## with a reducing agent, to obtain a compound of formula VII anda compound of formula X ##STR37## wherein R'" and R" are eachindependently selected from benzyl or lower alkyl, and then, b) reactingwith a reducing agent to reduce the azide group, and c) hydrolyzing theester groups,to obtain a compound of formula I.
 2. The process accordingto claim 1, further comprising, after step a):d) reacting the compoundof formula VII and the compound of formula X with trifluoromethanesulfonic acid to obtain a resultant, and then e) reacting the resultantof step d) in a base to obtain a compound of formula XXVI ##STR38## andf) treating with a gas selected from the group consisting of hydrogenand tritium gas and a mixtures thereof.
 3. The process according toclaim 1, further comprising, after step a):d) reacting the compound offormula VII and the compound of formula X with trifluoromethane sulfonicacid to obtain a resultant, and then e) reacting the resultant of stepd) with a reagent having an azide group in a polar, aprotic solvent, toobtain a compcwnd of formula XXVIII ##STR39##
 4. The process accordingto claim 1, further comprising, after step a): d) alkylating,alkenylating or benzylating the compound of formula VII and the compoundof formula X.
 5. A process for the preparation of a compound of formulaVII ##STR40## wherein R'" and R" are each independently selected frombenzyl or lower alkyl, comprising reacting a compound of formula IX##STR41## with a reducing agent, to obtain a compound of formula VII. 6.A process for the preparation of a compound of formula ##STR42## whereinR¹ is hydroxy, lower alkoxy, lower alkenyloxy, benzyloxy, hydrogen,deuterium or tritium,R¹¹ is hydrogen, deuterium, tritium, hydroxy oramino, and R² is hydrogen or tritium, or R¹ and R² form a bond,whichprocess comprises: a) providing a compound of formula VII, ##STR43##wherein R'" and R" are each independently selected from benzyl or loweralkyl and then, b) reacting with a reducing agent to reduce the azidegroup, and c) hydrolyzing the ester groups, to obtain a compound offormula I.
 7. The process according to claim 6, further comprising,after step a):d) reacting the compound of formula VII withtrifluoromethane sulfonic acid to obtain a resultant, and then e)reacting the resultant of step d) in a base to obtain a compound offormula XXVI ##STR44## and f) treating with a gas selected from thegroup consisting of hydrogen and tritium gas and mixtures thereof. 8.The process according to claim 6, further comprising, after step a):d)reacting the compound of formula VII with trifluoromethane sulfonic acidanhydride to obtain a resultant, and then e) reacting the resultant ofstep d) with a reagent having an azide group in a polar, aproticsolvent, to obtain a compound of formula XXVIII ##STR45##
 9. The processaccording to claim 6, further comprising, after step a): d) alkylating,alkenylating or benzylating the compound of formula VII.
 10. A processfor the preparation of a compound of formula ##STR46## wherein R¹ ishydroxy, lower alkoxy, lower alkenyloxy, benzyloxy, hydrogen, deuteriumor tritium,R¹¹ is hydrogen, deuterium, tritium, hydroxy or amino, and R²is hydrogen or tritium, or R¹ and R² form a bond,which processcomprises: a) providing a compound of formula X, ##STR47## wherein R'"and R" are each independently selected from benzyl or lower alkyl andthen, b) reacting with a reducing agent to reduce the azide group, andc) hydrolyzing the ester groups, to obtain a compound of formula I. 11.The process according to claim 10, further comprising, after step a):d)reacting the compound of formula X with trifluoromethane sulfonic acidanhydride to obtain a resultant, and then e) reacting the resultant ofstep d) in a base to obtain a compound of formula XXVI ##STR48## and f)treating with a gas selected from the group consisting of hydrogen andtritium gas and mixtures thereof.
 12. The process according to claim 10,further comprising, after step a):d) reacting the compound of formula Xwith trifluoromethane sulfonic acid anhydride to obtain a resultant, andthen e) reacting the resultant of step d) with a reagent having an azidegroup in a polar, aprotic solvent, to obtain a compound of formulaXXVIII ##STR49##
 13. The process according to claim 10, furthercomprising, after step a): d) alkylating, alkenylating or benzylatingthe compound of formula X.
 14. A compound of formula ##STR50##
 15. Acompound of formula wherein T is tritium.
 16. A compound of formula##STR51## wherein R" and R"" are each independently selected from benzylor lower alkyl.
 17. A method of controlling or preventing a neurologicaldisease or a psychiatric disorder comprising administering to a patientin need of treatment an effective amount of the compound of formula I-A.##STR52##
 18. The method according to claim 17, wherein the dosage isfrom about 1 mg to about 1000 mg per day.